DNA damage can elicit a variety of cellular responses including 1) inhibition of DNA replication, transcription and progression through the cell cycle, 2) cell death, and 3) mutagenesis. These biological consequences of DNA damage can perturb normal cellular function and impact health span. Organisms have evolved with genome safeguarding mechanisms, such as DNA repair pathways, to minimize the deleterious effects of DNA damage. Regardless, DNA damage and mutagenesis increase with age in a variety of tissues, thereby endangering health span. The decreased genetic integrity associated with older age corresponds to decreased base excision repair activity, and decreased DNA polymerase -beta activity/abundance in some tissues. The purpose of the proposed studies is to determine the extent to which DNA polymerase-beta dependent base excision repair (BER) contributes to genomic integrity, health span and lifespan. Lacking a proofreading activity, DNA polymerase-beta has a relatively low fidelity. Brain tissue in transgenic mice carrying a mutational reporter transgene do not display an increased mutant frequency with older ages, but mice do exhibit decreased BER and a reduced DNA polymerase-beta activity in brain of older animals. In contrast, male germ cells obtained from young adult DNA polymerase-beta heterozygous knockout mice display an increased spontaneous mutant frequency. These and other data suggest that changes in DNA polymerase-beta activity could mediate different effects among mammalian tissues. The overall hypothesis to be tested is that modulation of DNA polymerase beta abundance/activity will have differential effects among tissues relative to age. Mouse models, and cell lines derived from the mouse models, with normal, enhanced or reduced DNA polymerase-beta expression/activity will be used to examine the potentially protective and deleterious effects of altered DNA polymerase-beta activity. Genetic integrity, apoptosis, and pathology will be examined using a variety of molecular, biochemical and cell biological approaches.